The increased prevalence of type 2 diabetes mellitus (also referred to herein as T2DM or type 2 diabetes), together with its burden of patient suffering and societal costs, underscores the importance of finding effective strategies for both treatment and prevention. T2DM is characterized by high blood glucose levels caused by a lack of insulin or the body's inability to efficiently use insulin. Two clinical constructs for identifying individuals at high risk of future T2DM are prediabetes and metabolic syndrome (MetS). Prediabetes is a state of dysglycemia characterized by impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A diagnosis of prediabetes may be made if an individual's glucose is higher than normal but not high enough to be diagnosed as diabetes. It is estimated that 79 million Americans aged 20 years or older have prediabetes, with 25% progressing to T2DM within 3-5 years (Nathan, et al. Diabetes Care. 2007; 30(3):753-759). ENREF4 T2DM is associated with abdominal obesity and insulin resistance (diagnostic criteria were established by the Advanced Treatment Panel III of the National Cholesterol Education Program). There are a number of risk factors that increase an individual's risk for T2DM including, for example, being over age 45, being overweight or obese, having a parent, brother or sister with diabetes, a family background that is African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, or Pacific Islander, having a history of gestational diabetes, giving birth to a baby weighing more than 9 pounds, blood pressure of 130/85 or 140/90 or higher, HDL lower than 35 or lower than 40 (for males) or lower than 50 for females or triglyceride level above 150 or above 250, inactive lifestyle, polycystic ovary syndrome, a previous diagnosis of prediabetes, for example HbA1c level of 5.7 to 6.4%, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), another clinical conditions associated with insulin resistance, such as a condition called acanthosis nigricans, characterized by a dark, velvety rash around my neck or armpits, or a history of cardiovascular disease. The more of these risk factors present in a patient the higher the patient's risk of developing T2DM. HbA1c refers to glycated haemoglobin (A1c), which identifies average plasma glucose concentration and can be used to get an overall picture of what an individual's average blood sugar levels have been over a period of time.
MetS is a cluster of risk factors for cardiovascular disease including the following risk factors (1) a large waistline (at least 102 cm or 40 inches for males and at least 88 cm or 35 inches for females), also referred to as abdominal obesity, (2) high triglyceride levels (greater than 150 or 250) or using medicine to treat high triglycerides, (3) low HDL cholesterol levels (lower than 35 or lower than 40 (for males) or lower than 50 for females) or using medicine to treat low HDL cholesterol, (4) high blood pressure (above 130/85 or above 140/90) or using medicine to treat high blood pressure, and (5) high fasting blood sugar (also referred to as impaired fasting glucose (IFG)) or using medicine to treat high blood sugar ((See Alberti K G, et al., Circulation 2009; 120(16): 1640-1645; Bakris G, et al., Diabetes Obes Metab. 2009; 11(3):177-187; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001; 285(19):2486-2497; and Grundy S M, et al. Circulation 2005; 112(17):2735-2752). A diagnosis of MetS generally required a diagnosis of at least three of the five metabolic risk factors listed above. Individuals with MetS are at a 5-fold increased risk of developing T2DM (Alberti K G, et al. 2009). Because IFG is one of the traits used to identify MetS, overlap with criteria for prediabetes exists, and the risk of progression to T2DM is further increased in individuals who satisfy the criteria for both MetS and prediabetes. Lorenzo C, et al., Diabetes Care. 2003; 26(11):3153-3159. Thus, effective treatment of these at-risk individuals is important for the prevention of T2DM.
Sustained loss of 5% to 10% of body weight in obese and overweight patients has proven to be effective in preventing progression from prediabetes and MetS to T2DM and also ameliorates the cardiometabolic disease process, as shown by an increase in insulin sensitivity and a reduction in cardiovascular disease risk factors. However, achieving sustained weight loss at a clinically meaningful level sufficient to reduce risk remains a challenge for many patients. The primary approach to treating obesity and its related complications involves lifestyle modifications, including reductions in caloric intake (by 500-4000 calories/day) combined with increases in physical activity. Bariatric surgery can also be an effective weight-loss option for patients meeting specific criteria and may reduce the incidence of T2DM, Colquitt J L, et al., Cochrane Database Syst Rev. 2009; 15(2):CD003641, Hussain S S, Bloom S R, Postgrad Med. 2011; 123(1):34-44 and Carlsson L M, et al., N Engl J Med. 2012; 367(8):695-704 but the approach entails risks associated with surgery, nutritional deficiencies, and weight regain in some patients. Kofman M D, et al., Obesity (Silver Spring). 2010; 18(10): 1938-1943.
In patients for whom lifestyle changes alone are insufficient and bariatric surgery is not an option, pharmacotherapies may be considered. Phentermine and topiramate extended-release (PHEN/TPM ER; QSYMIA®; VIVUS, Inc., Mountain View, Calif.) has been shown to induce significant weight loss when combined with lifestyle modification in overweight/obese adults. See, for example, Allison D B, et al., Obesity (Silver Spring), 2012; 20(2):330-342. The CONQUER study assessed effectiveness of PHEN/TPM ER for weight loss in overweight/obese adults with two or more weight-related comorbidities over 56 weeks (ClinicalTrials.gov, NCT00553787)(Gadde K M, et al., Lancet. 2011; 377(9774):1341-1352) and was followed by SEQUEL, a 52-week blinded extension study (ClinicalTrials.gov, NCT00796367)(Garvey W T, et al., Am J Clin Nutr. 2012; 95(2):297-308). In order to assess the ability of PHEN/TPM ER to reduce progression to T2DM and improve manifestations of cardiometabolic disease in patients at high risk of developing T2DM, a subpopulation of patients meeting the criteria at baseline for prediabetes and/or MetS who elected to enroll in SEQUEL was analyzed.
In addition to being related to incidence of various diseases, obesity can increase the risk of death from hypertension, dyslipidemia, diabetes, such as type II diabetes mellitus, coronary artery disease, heart disease, stroke, gallbladder disease, osteoarthritis, liver disease, and cancers, such as endometrial, breast, prostate, and colon cancers (see, for example, Pi-Sunyer et al. Postgrad Med 2009:121:21-33).
Topiramate, a sulfamate-substituted monosaccharide with the chemical name 2,3,4,5-bis-O-(1methyletylidene)-β-D-fructopyranose sulfamate, has been reported for use in treating obesity and promoting weight loss, for example, in U.S. Pat. Pub. 2009/0304785, and is also marketed for treating migraine headaches and seizure related disorders. A variety of dosages of topiramate can be used for these purposes, depending on the weight, age, gender, and other characteristics of the subject. Although efficacious for these purposes, topiramate is known to have harmful side effects in some subjects. Furthermore, some subjects do not respond to topiramate treatment for obesity. Thus, there is a need for a dosing regimen for topiramate that minimizes subjects' exposure to topiramate while providing one or more indications of whether a particular subject is likely to experience harmful side effects and/or respond to topiramate treatment. The embodiments described herein can meet these and other needs.